For over 100 years, myocardial stiffness has been known to be a central parameter of cardiac function and to underlie multiple diseases. Abnormal stiffness is the key pathologic cause of the two major forms of heart failure: 1). increased global stiffness causes poor ventricular filling, leading to heart failure with normal ejection fraction (HFNEF), and 2). myocardial infarction alters regional stiffness, triggering left ventricular (LV) remodeling and heart failure with reduced ejection fraction (HFREF). Together, these two mechanisms account for the majority of incident heart failure, which in turn accounts for $39.2 billion in overall medical costs per year and has been called a new epidemic for the 21st century. Although direct measurement of myocardial stiffness could be an important tool for assessing cardiovascular disease, there is currently no non-invasive method to assess myocardial stiffness. The effect on clinical research has been profound because non-invasively measuring a disease process is key to creating effective treatments for that disease. To date, no effective treatment for HFNEF has been developed and heart failure overall continues to have a five year mortality of approximately 50%. Our group has developed a novel, non-invasive measure of myocardial stiffness called Cardiac Magnetic Resonance Elastography (CMRE). In CMRE, non-invasive mechanical drivers, applied to the chest wall, transmit waves to the myocardium. A phase gradient magnetic resonance imaging pulse sequence, synchronized to the externally-applied waves, encodes the wave displacement information. The wave displacements are then converted to myocardial stiffness maps through a mathematical process called inversion. Each stage of CMRE is difficult to perform in a thin-walled, beating, internal organ such as the heart. Therefore, we propose to develop novel CMRE drivers, sequences and inversions, which will make CMRE applicable in humans. We will validate the CMRE stiffness measurements against in vivo pressure/volume derived myocardial stiffness in an animal model of HFNEF and against ex vivo mechanical testing in an animal model of myocardial infarction -- the most common cause of HFREF. If successful, this proposal would lead to the development of CMRE as a robust clinical and research tool for the non-invasive measurement of myocardial stiffness. CMRE could lead to improved diagnosis in heart failure and could be used to guide creation of more effective heart failure treatments. PUBLIC HEALTH RELEVANCE: Stiffness of the heart muscle is an extremely important marker of heart disease. However, the heart's stiffness can currently only be measured invasively by placing a catheter into the heart and making pressure measurements. Because this is difficult to do, there is limited understanding of diseases caused by increased heart stiffness. In particular, a very important disease called heart failure with normal ejection fractin has been hard to diagnose and treat. A new type of MRI scan has been developed that can measure heart muscle stiffness. With this new scan, doctors might be able to diagnose heart failure with normal ejection fraction and measure the heart's response to medication.